Expert Commentary

Drs. Steven G. Deeks and Satish Pillai discuss whether there might be a cure for HIV infection in the future.

SP: What do you think have been the most salient developments that have refocused the attention of the research community towards a cure for HIV in the last couple of years?

SD: The obvious example is the Berlin patient. His story galvanized not just the existing HIV-research community but a lot of people outside the HIV community that a cure for HIV infection might be possible.

This happened at about the time that I think the HIV community began to realize that there are significant limitations to long-term therapy. Even though these drugs work great, there is a large subset of people who either can't take drugs daily or do not have the resources to access drugs daily. This whole concept that we're going to be able to treat people indefinitely, for decades, is now being widely questioned.

These two things happened at the same time. You had a perception that we needed a totally new way of treating this disease that did not require life-long therapy. You had a case that proved a cure was possible. This happened about 3 or 4 years ago.

SP: Just two additional questions on the Berlin patient. What is your opinion of the status of his cure? Would you consider him to be completely cured? Do you consider it to be a functional cure? Do you consider it to be a sterilizing eradication?

SD: Let's back up here just a little bit. How do we define a cure? There are generally two ways to find a cure. One is where we basically go in and surgically or medically remove every last replication competent virus in the body. That is the ideal outcome. This is often referred to as a sterilizing cure, is the optimal outcome.

Then there is this concept of functional cure, where one says, "You know, the virus is going to persist forever; we're never going to get rid of it. But let's train the immune system or some other mechanism to keep the virus down in the absence of therapy."

Then there is this concept of functional cure, where one says, "You know, the virus is going to persist forever; we're never going to get rid of it. But let's train the immune system or some other mechanism to keep the virus down in the absence of therapy."

The question that has been debated to a certain degree ever since the Berlin patient case was published in The New England Journal of Medicine is, "What is the nature of this cure? Has the virus been completely removed?" The Berlin patient, Mr. Timothy Brown, moved to San Francisco about 2 or 3 years ago and graciously agreed to participate in our studies, which ended up being quite extensive. We did everything possible to find enough biologic specimens to see if there was any virus left, and we distributed these tissues throughout the world to people who were expert at finding low levels of virus. At the end of the day, I think most of us came to the conclusion that there may be remnants of the virus, but proving that they are real is not possible with current methodologies. Importantly, we found no evidence that there is any virus around that could replicate. We also found no evidence of virus that was actually causing enough harm that the immune system detected it. We found evidence that the antibodies to the virus were waning to the point where he is almost HIV negative on standard tests. Based on all that, and the fact that he has done well clinically, we believed he may indeed have had a sterilizing cure--a final, definitive cure. Proving a negative is impossible, however.

SP: One thing you mentioned is the functional cure, where the immune system is trained to keep the virus at bay indefinitely in the absence of antiretroviral therapy, correct?

SD: Right.

SP: Would you consider elite controllers to be examples of functional cures?

SD: Oh, yes. Dr. Hiroyu Hatano in our group did a very nice study recently where she took a group of HIV-infected adults who have not been on drugs since they were infected and who were controlling their virus naturally. Some would meet a standard definition of having been cured of their infection in that they had no detectable virus using standard assays. She gave them antiretroviral drugs and showed as a consequence that there was an immediate drop in the amount of virus and the inflammatory response of the virus declined. This proves that elite controllers have virus that can replicate and hence, if one considers them cured, then they have a functional cure in which some host mechanism controls the virus indefinitely.

SP: The reason I brought that up is that, if elite controllers are examples of a functional cure and your recent experiment with Dr. Hatano demonstrated there were some additional benefits, the outcomes that you registered were: 1) Using ultra-sensitive assays, there was still reduction in HIV viral load, and 2) There was a reduction in activation.

SD: There was reduction in viral load in blood and tissues. There was reduction in activation, and there was a reduction in the level of HIV antibodies.

SP: If that is an example of functional cure, and by treating them with antiretroviral therapy, you can still improve their virologic and immunologic scenario, what does that tell us about a functional cure? Does that mean a functional cure is still relevant or it is not really a meaningful target?

SD: Well, no ... If you are an elite controller and you have been functionally cured--that is, you have some way to control the virus on your own--that's great, right? This is better than not controlling the virus. But is that as good as being HIV negative? No. A little bit of virus can cause a little bit of harm, and a little bit of harm over a period of decades could be a lot of harm. And so we are of the mindset that, even though elite controllers have a little bit of virus, not enough that you worry about it on a day-to-day basis, over a period of years to decades, some HIV-associated harm may become apparent. This harm is likely due to chronic inflammation and might include early heart disease. I don't think a functional cure is really an ideal outcome.

SP: I have another question that derives from the Berlin patient. You've done some very systematic, comprehensive, exhaustive experiments to look for residual virus in this patient. The data looked very promising. I think the million-dollar question is how generalizable are the results that have been obtained by studying the Berlin patient, because it's a very unique case. Could you detail why you think maybe some of these observations are generalizable and also maybe why you think that these data are not generalizable because of the uniqueness of his history?

SD: There have been several other potential cures lately. The baby who was apparently cured with early antiretroviral therapy has generated lots of excitement. As with the Berlin patient, the group studying that baby is struggling to determine if the virus was completely removed. They did a fair amount of extensive work on the baby a couple years after she was born, and found maybe remnants of nucleic acid. Is it real? Is it not real? And there are some cases in Boston in which they're struggling with this concept of whether bone-marrow transplant was curative.

As we move forward with these cure studies and all these examples of where a cure might have actually occurred, all the groups are confronted with the same problem: How do you prove it? How do you actually prove that somebody was cured? How do you prove a negative, right? How do you prove the absence of the virus? This is a big challenge.

SP: Yes, but at least with the adult cases, they all have a common feature whereby they were patients who underwent bone-marrow transplantation. Do you think that the idea of ablation of the immune system following bone-marrow transplantation could ever be a scalable strategy to treat HIV-infected individuals?

SD: I do not ever see a typical HIV-infected adult getting a bone-marrow transplant from an allogeneic donor just to cure HIV. The risks are too great. But I do believe that, as a consequence of what we learned with the Berlin patient, you could do autologous cell therapy. You could take stem cells from a person, modify them genetically, and then infuse them back in, in a way that would be safe and affordable, and potentially scalable.

SP: I think that, motivated by the Berlin patient and these other successes that you have discussed, there has been a range of experiments to try to eliminate the latent reservoir in infected individuals.

SD: Sure.

SP: Could you discuss your evaluation of these experiments and what we have learned from strategies to eliminate the latent reservoir?

SD: The big barrier to a cure is that there are cells that lie dormant, survive for decades, and contain hidden within them the virus. That is the primary limitation, and the primary goal of cure research is to get rid of it. One approach that is quite attractive to many investigators is this concept of "shock and kill." One uses a drug to shock the cells to force the virus out and then one hopes the cell will die, or one modifies the immune system to make sure all virus-producing cells die.

We are at the beginning of that, and we are just now starting with the shock part. There have been some examples. There are a couple of high-profile presentations recently showing that certain drugs that alter the DNA, that modify the chromatin that increase the cell's capacity to transcribe DNA, can, in fact, force the virus out of its hiding place. Whether that leads to any meaningful outcome, no one knows, but it proves the concept. At least the shock part, shocking it out of its hiding place, is theoretically possible.

SP: This might be slightly hyper-technical, but the underlying idea with the shock approach would be that you force cells that are harboring viruses to purge their viral cargo.

SD: Yes.

SP: But part of that idea is that those cells are fated for death after they release their virus, right?

SD: Yes.

SP: But if there is some question as to whether that actually happens...

SD: No one knows their fate. In theory, the virus itself is harmful to the cells, or the immune system sees a cell now making virus and it kills the cell. But whether or not this is happening, and there are some data suggesting that perhaps it is not, that's data in the test tube. What actually happens in people, no one really knows.

SP: Another concept that I think is directly relevant to the reservoir and to destroying the reservoir is whether there is ongoing replication of HIV during suppressive antiretroviral therapy. What is your take on that? Do you think there is ongoing replication, and if so, how is it relevant to the eradication strategies?

SD: It's probably one of our contentious issues in the field. The fundamental question is whether current drugs block every virus in every person every day of the year, and there are data suggesting that might be happening, and there are data suggesting that the virus is actually still dividing, growing, replicating at low levels. I believe the latter; I think it is ongoing.

The issue is, why is it important? It's important not because it is causing any great harm by itself--it really is scant amounts. It is important because it's going to be hard to cure someone, particularly with the "shock and kill" approach--where you are forcing the virus out of its hiding place--if that virus continues to just find another hiding place. We have to shut the virus down completely, I think, and then do the "shock and kill" approaches, or gene therapy, or whatever.

SP: In terms of characterizing the latent reservoir, what do you think are the most critical questions now, in terms of characterizing where the virus is and how it continues to persist?

SD: One of the big questions in the field is actually, "Where is the virus?" We can find it in the blood, but that's probably not the major source. There is some emerging data from monkeys that have been put on treatment. They do autopsy studies and look everywhere in the monkeys, and a lot of the virus is in lymph nodes, which makes sense--that's where the T-cells live--and perhaps in the spleen, and some in the brain, but really, this is a big issue for the clinical researchers. The blood itself is probably not an ideal way to sample a reservoir. You have to go where the virus is and that's the lymph nodes, gut, and so forth.

SP: You're part of the group called The International AIDS Society Scientific Working Group on HIV Cure. What has been your process and what are your key recommendations so far?

SD: A few years ago, The International AIDS Society decided to enable cure work in a big way, so they assembled a group of about 40 scientists who met over a period of a year or two, and we came together and came up with a roadmap, a plan to achieve cure. This plan was published last summer, got a lot of attention, and that's where we are now. This working group is more or less disbanded, but some of the efforts of the IAS continue, in terms of trying to make sure that certain aspects of cure work are ongoing--including addressing ethical issues and cost effectiveness--plus we're sponsoring an annual meeting to try to help communication among those doing cure work.

SP: What are some disadvantages or political or ethical challenges of researching the possible HIV cure?

SD: Well, there are scientific issues that we have already discussed, and there are also some ethical issues that are interesting.

The Berlin patient case, right? Mr. Brown is happy that he was cured of HIV, no question about it, but would he do it again? If he were healthy and didn't have to have a bone-marrow transplant, probably not. These heroic interventions are just far too toxic. Most people on therapy are doing well. As long as they can have access to drugs, they still will be healthy for years, and decades.

The fundamental issue is that everyone wants a cure, no one wants to deliver these drugs forever, but no one is dying from the disease anymore. You don't want to intervene with a potential drug that is toxic, or too toxic. You don't want to do any harm.

On the other hand, we are probably not going to cure anyone with aspirin. We are going to need drugs that perhaps have some risks associated with them. Balancing the risks and the benefits in a group of people who are doing well as long as they are getting the drugs is a challenge.

SP: Given the information from CROI, does that refocus research more on acute infection in your mind?

SD: Oh, yes! One of the major messages from the CROI--this is from the baby case and from a cohort in Thailand--is that if you intervene super early, within days of being exposed, treatment itself may end up being curative. If the virus gets into someone, and it finds its way into cells that are destined to die anyway, who cares? Those cells are not going to live; the virus will just die with it. If you get someone into care really early, and get them on a very effective regimen, you may be able to prevent seeding of the so-called latent reservoir.

I think that is what happened in the baby. I don't know; that is what I think. The treatment prevented the establishment of this reservoir. This also may be happening in adults. There is a study from Thailand in which a group of people got on therapy remarkably early, and they didn't have much virus in some of these longer-lived cell populations.

SP: Do you think universal early antiretroviral therapy is a critical step in setting the landscape for curative strategies?

SD: Oh, yes! There is a cohort of people over in Paris, the VISCONTI cohort. This is a group of people--it's highly controversial but I tend to believe it's true--who, as a consequence of going on therapy really early and staying on it for four years or so, basically were functionally cured. They stopped drugs and they have done well for years without drugs. The mechanism is unknown. But we never see this when people start therapy late.

SP: Have you ever seen that in people who started therapy early within the San Francisco population?

SD: We had a few people like this, but they may have been elite controllers and they may have done this without therapy at all. We don't really know. Some people do this spontaneously, and it's a big problem trying to understand the rare cases of people who seem to go on therapy, stop it after a few years, and do well--does that mean the treatment helped them in some way or were they destined to do well? Would this have happened had they not used therapy?

SP: Well, you can look at frequencies on average, something like 0.3% of the patients are elite controllers.

SD: When the French looked at this question, the figured that about 1% of people become elite controllers without therapy, while about 10% of people who go on therapy really early will be able to eventually stop therapy and remain free of detectable virus for years.

SP: Do you think pharmaceutical companies are fully behind research for a cure, given the huge profits they make from long-term combination therapy?

SD: It's a great question. People don't believe me when I say this--maybe I'm naive--but yes, I think certain companies are genuinely interested in finding a cure. The companies that have the most profitable drugs tend to be the ones that are most heavily invested in cure now. They are doing this for obvious humanitarian benefits. Also, we we will soon see in the hepatitis C world, there's a lot of money to be made in curing chronic diseases. It's going to cost a lot of money to develop a cure, so we are fortunate that there is potential profit to be made.

No one believes a cure is going to be coming out any time soon, but by the time the cure is here, many of the current antiretroviral drugs will be generic. So I don't think there is any disincentive for companies just to invest in this. In fact, I think there is a great incentive.

SP: The critical difference between hepatitis C and HIV is that there aren't currently available maintenance therapies that would be rendered obsolete.

SD: Right, but those maintenance therapies are all going to be generic in a few years. All the profits being made right now on those drugs aren't going to be generating profits for decades. It makes great sense for these companies to get into the cure world because, when generics are available, it's going to be tough for these companies to come up with newer antivirals that are expensive when these other ones are much cheaper.

SP: I have another question on the same wavelength. In this suboptimal funding environment where there are very limited and finite resources available to conduct research, do you think there's a conflict of interest between research on curative strategies versus the research on prophylactic vaccines? And what sort of interaction do you think there is between those two fields?

SD: Yes, this is a challenging issue. Funders have to decide--particularly the NIH--how to direct money. The amount of money going to cure work is relatively small now, but it's hopefully going to grow. Cure work hasn't really affected the other agendas, but this might become an issue in the future.

SP: In terms of the impact on the epidemic, it seems like a lot of data suggest that the bulk of transmission events occur early in infection. Do you think that the development of a cure could have a significant impact on the epidemic at large, or do you think it's more tailored towards benefits that are directed at the single individual?

SD: We don't really want to have a handful of Berlin patients. That's not going to change the world. We all want to cure people in a big way with drugs that could be given for a few months everywhere in the world. And the best prevention is to cure someone. If you are cured, you're not going to infect others. So I think a cure is ultimately the best way to deal with therapeutic issues as well as the financial issues and the prevention issues.

SP: That's pretty good closure right there. Thanks.

Steven Deeks, MD, Professor, UCSF Positive Health Program at San Francisco General Hospital